Developmental Regulation of Follicle-Stimulating Hormone Receptor Messenger RNA Expression in the Baboon Fetal Ovary1

Abstract

In the adult ovary, pituitary FSH via interaction with its receptor (FSHR) is required for follicular maturation and granulosa cell development. In humans and nonhuman primates, the pool of follicles available for adult ovarian function is established in utero. However, our understanding of the ontogeny and developmental regulation of FSHR in the ovary of the primate fetus is incomplete. Our goal was to determine whether the baboon fetal ovary expresses the full-length FSHR mRNA transcript and whether levels are developmentally regulated. Fetal ovaries were obtained at mid (Day 100) and late (Day 165) gestation (term = Day 184) from untreated baboons and on Day 165 from baboons in which fetal estrogen levels were either decreased by >95% by treatment with the aromatase inhibitor CGS 20267 or restored to 30% of normal by treatment with CGS 20267 plus estradiol benzoate administered s.c. to the mother on Days 100-164. The full-length 2088-base pair FSHR mRNA transcript was expressed in ovaries of adult and fetal baboons untreated or treated with CGS 20267 or CGS 20267 and estrogen. Mean (+/-SEM) FSHR mRNA levels (ratio of FSHR mRNA:18S rRNA), quantified by reverse transcription polymerase chain reaction, were increased (P < 0.05) 2-fold between mid (0.34 +/- 0.06) and late gestation (0.76 +/- 0.07), an increase prevented (P < 0.05) in estrogen-depleted baboons (0.44 +/- 0.10) and partially restored by treatment with CGS 20267 and estrogen (0.58 +/- 0.16). We previously showed that the number of follicles/0.33 mm2 in fetal ovaries of untreated baboons in late gestation was reduced 50% by treatment with CGS 20267 and restored to normal in baboons treated with CGS 20267 and estrogen. Thus, when corrected for the number of follicles/0.33 mm2, FSHR mRNA levels were similar in baboon fetal ovaries untreated (0.010 +/- 0.001) or treated with CGS 20267 (0.009 +/- 0.002) or CGS 20267 and estrogen (0.007 +/- 0.003). We conclude that estrogen plays a major role in regulating ovarian FSHR mRNA expression in the primate fetus, and that the developmental increase in FSHR mRNA levels reflects the estrogen-dependent increase in folliculogenesis (i.e., increased number of granulosa cells and oocytes).

Regulation of Baboon Fetal Pituitary Prolactin Expression by Estrogen1

“…Thus, fetal follicle-stimulating hormone levels were negatively correlated with ovarian folliculogenesis, declined between mid and late gestation, and remained elevated in estrogensuppressed animals in which follicle formation was markedly reduced [10]. The results of the current study show that in female but not male fetuses, fetal pituitary LH expression also declined between mid and late gestation and was prevented in estrogen-suppressed animals; these findings further support this hypothesis.…”

“…We showed previously that the estrogen-dependent ontogenesis in fetal ovarian follicle formation did not appear to reflect an action of fetal pituitary gonadotropins [10]. Thus, fetal follicle-stimulating hormone levels were negatively correlated with ovarian folliculogenesis, declined between mid and late gestation, and remained elevated in estrogensuppressed animals in which follicle formation was markedly reduced [10].…”

“…Thus, we showed that fetal serum gonadotropin levels were inversely correlated with follicle development, and thus were higher at mid than at late gestation. Moreover, gonadotropin levels remained elevated in late gestation in estrogen-suppressed baboons and decreased in animals treated with letrozole and estradiol [10]. In addition, mRNA levels of fetal pituitary ACTH precursor proopiomelanocortin were not significantly altered in late gestation in estrogen-suppressed fetuses [7].…”

Regulation of Baboon Fetal Ovarian Development by Placental Estrogen: Onset of Puberty Is Delayed in Offspring Deprived of Estrogen In Utero1

“…Serum LH and FSH levels were measured by RIA using antibodies/reagents and procedures established for the baboon, as described previously [10,32]. The baboon FSH and LH RIA had intra-assay coefficients of variation of 5.4% and 6.2%, respectively, interassay coefficients of variation of 6.9% and 4.5%, respectively, and a minimal detectable dose of 0.009 ng/tube [10,32].…”

“…Thus, in baboons in which estrogen was suppressed by treatment with the aromatase inhibitor letrozole during the second half of gestation, the number of primordial follicles formed in the fetal ovary was reduced by more than 50% [6], and the majority of follicles that developed contained unhealthy oocytes [7]. Additional studies showed that this critical action of estrogen most likely is elicited directly on the fetal ovary, which expresses estrogen receptor (ER) a/b [8,9], and not indirectly via fetal pituitary gonadotrophin support, fetal ovarian follicle-stimulating hormone (FSH) receptor expression [10], or fetal pituitary prolactin secretion [11]. Collectively, these observations, plus the fact that fetal ovarian folliculogenesis and oocyte integrity were normal in baboons treated with letrozole and estradiol, support our hypothesis that placental estrogen programs fetal ovarian development and regulates formation of the stockpile of healthy follicles critical for long-term survival [5,6] and presumably reproductive function in adulthood.…”